ArticlePloS one2013
Distinct internalization pathways of human amylin monomers and its cytotoxic oligomers in pancreatic cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- Pomegranate peel, chokeberry leaves and Ironwort extract as novel natural inhibitors of amylin aggregation and cellular toxicity in pancreatic β cells.Biophysical chemistry · 2024Article
- Contraction of human brain vascular pericytes in response to islet amyloid polypeptide is reversed by pramlintide.Molecular brain · 2023Article
- Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.Molecules (Basel, Switzerland) · 2022Review
- Amyloid Beta Is InternalizedFrontiers in molecular neuroscience · 2022Article
- Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.Communications biology · 2021Article
- Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?International journal of molecular sciences · 2020Review
- Effect of IAPP on the proteome of cultured Rin-5F cells.BMC biochemistry · 2018Article
- Functional proteasome complex is required for turnover of islet amyloid polypeptide in pancreatic β-cells.The Journal of biological chemistry · 2018Article
- Membranes as modulators of amyloid protein misfolding and target of toxicity.Biochimica et biophysica acta. Biomembranes · 2018Review
- Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin evoked redox stress and apoptosis in pancreatic beta-cells.Biochimica et biophysica acta. Biomembranes · 2018Article
- No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases.Biological reviews of the Cambridge Philosophical Society · 2018Review
- A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells.International journal of molecular sciences · 2018Article
- Amylin and diabetic cardiomyopathy - amylin-induced sarcolemmal CaBiochimica et biophysica acta. Molecular basis of disease · 2018Article
- To What Extent Are the Terminal Stages of Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome Actually Driven by a Prion/Amyloid Form of Fibrin?Seminars in thrombosis and hemostasis · 2018Review
- RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity.The Journal of clinical investigation · 2018Article
- The Molecular Physiopathogenesis of Islet Amyloidosis.Handbook of experimental pharmacology · 2018Review
- Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer's disease.Neuroscience · 2017Review
- Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Amylin alters human brain pericyte viability and NG2 expression.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- Proteasome regulates turnover of toxic human amylin in pancreatic cells.The Biochemical journal · 2016Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤ 100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin's molecular forms, thereby serving a cyto-protective role in these cells.
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